Sigma binding site agents

ABSTRACT

Sigma binding site agents having the formula ##STR1## which are useful to inhibit sigma binding site-induced activity, pharmaceutical compositions including these agents, and methods of using these agents to inhibit sigma binding site-induced activity in mammals. Also disclosed are novel intermediates useful in preparing the presently invented agents.

RELATED APPLICATION

This application is a Continuation-in-Part of U.S. application Ser. No.07/533,127, filed Jun. 4, 1990, now abandoned, the contents of which arehereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel compounds that are sigma binding siteagents.

2. Background Information

Use of drugs with well-demonstrated effectiveness in treatment ofpsychiatric disorders has become widespread over the last thirty years.Presently about twenty percent of the prescriptions written in theUnited States are for medications intended to change mood, thinking, orbehavior. Neuroleptic agents such as chlorpromazine and haloperidol arethe primary medications used to treat schizophrenia and other psychoses.Most of the numerous clinically effective antipsychotic drugs currentlyavailable are dopamine (D₂) receptor antagonists and produce essentiallythe same spectrum of adverse effects. Examples of adverse effectsinclude extrapyramidal side effects such as various dystonias which mayresemble Parkinson's disease. Tardive Dyskinesia, characterized byinvoluntary movements consisting of sucking and smacking of the lips,lateral jaw movements, and fly-catching dartings of the tongue, is aserious and potentially irreversible adverse effect which occurs in upto twenty percent of patients treated with currently availableantipsychotic agents.

The recently identified central nervous system sigma binding sites arepotential targets for development of antipsychotic drugs that lack theadverse effects associated with available D₂ antagonists. Sigma bindingsites were initially postulated by Martin et al., J. Pharmacol. Exp.Ther., 197: 517-532, 1976, to explain the psychotomimetic effectsof(+)-benzomorphans such as N-allynormetazocine (SK&F 10047). It wassubsequently demonstrated that sigma sites could be selectively labeledby the ligands [³ H]ditolylguanidine (DTG) and [³ H](+)-3-(hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP]. Bothpsychotomimetic agents, such as the (+)benzomorphans and PCP, andcertain antipsychotic drugs, including haloperidol, displace [³ H]DTGand [³ H](+)-3-PPP from sigma sites. Because haloperidol reverses thestimulant and psychotomimetic effects of SK&F 10047 and PCP, it has beenargued that haloperidol may be a sigma "antagonist" and that the sigma"antagonist" activity of this and related agents may contribute to theirantipsychotic effects. Thus, a selective sigma "antagonist" that, unlikehaloperidol, is relatively inactive at dopamine receptors could evidenceantipsychotic activity without producing extrapyramidal side effects ortardive dyskinesias associated with currently available dopamineantagonist neuroleptics.

Rimcazole is the first sigma-selective antipsychotic for which resultsof a substantial number of clinical trials have been reported. Althoughrimcazole has shown some effectiveness in treating schizophrenia, it isonly moderately potent at sigma sites and has been shown to induceseizures. Chouniard, G. and L. Annable, Psychopharmacol. 84: 282-284(1984); Guy, W. et al., Drug Dev. Res. 3: 245-252 (1983). Remoxipride,another site binding agent which has been tested in humans, also hassignificant D₂ blocking potency. Thus, there remains a need forsigma-selective agents which effectively treat psychoses withoutproducing adverse effects.

It has now been found that certain derivatives of chromone(4H-1-benzopyran-4-one) compounds (Formula I, below) are potent andselective for sigma binding sites and, like haloperidol, antagonize thestimulant/psychotomimetic effects of the dopamine agonist, amphetamine,and presumed sigma agonists such as PCP. For this reason, the novelchromones, like haloperidol, will be referred to as sigma antagonists.Note that the designation of these agents as sigma antagonists refers tothe in vivo pharmacological profile of the compounds, not to themechanism of action at sigma receptors/binding sites. Also, "receptor"as used herein refers to true, membrane-bound receptors and to otherbinding sites.

Jesthi, P. K. et al. describe β-diethylaminoacetoxy, β-aminoethoxy, andβ-diethylaminoethoxy flavone derivatives found to possess antispasmodicand antihistaminic properties. J. Indian Chem. Soc. 42: 105-108 (1965).

German Patent No. 1,054,091 (1959) discloses a series ofN-substituted-2-phenyl-7-aminoalkoxy chromone compounds reported to havevasodilator activity. U.S. Pat. No. 3,810,896 (1974) discloses various4-[ω-(flavone-7-yloxy)]-alkyl piperazine compounds reported to haveantiinflammatory and antiedematous action.

U.S. Pat. No. 4,678,787 (1987) discloses 4H-1-benzopyran-4-ones andtheir sulfur analogues for treatment of psychosis includingschizophrenia.

SUMMARY OF THE INVENTION

The present invention resides in the discovery that certain derivativesof chromone compounds of Formula I (below) are potent and selectivesigma receptor binding site agents which, like haloperidol, antagonizethe stimulant/psychotomimetic effects of dopamine agonists, such asamphetamine, and presumed sigma agents such as phencyclidine. Thesecompounds are useful as antipsychotic drugs.

Illustrative compounds of the invention include:

6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methyl-2-phenyl-4H-1-benzopyran-4-one,

6-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-4H- 1-benzopyran-4-one,

6-[8-(dimethylamino)octoxyl]-2-phenyl-4H-1-benzopyran-4-one,

6-[5-(dimethylamino)pentoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[6-(dimethylamino)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[6-(2-hydroxyethylmethylamino)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[7-(dimethylamino)heptoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[9-(dimethylamino)nonoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[9-(4-methylpiperazinyl)nonoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[10-(dimethylamino)decoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[5-(4-hydroxypiperidinyl)pentoxy]-2-(3-methoxyphenyl)-4H-1-benzopyran-4-one,

6-[5-(4-hydroxypiperidinyl)pentoxy]-2-(4-methoxyphenyl)-4H-1-benzopyran-4-one,

2-(3,4-dimethoxyphenyl)-6-[5-(4-hydroxypiperidinyl)pentoxy]-4H-1-benzopyran-4-one,

2-cyclohexyl-6-[5-(4-hydroxypiperidinyl)pentoxy]-4H-1-benzopyran-4-one,

6-[5-(dipropylamino)pentoxy]-2-(3-methoxyphenyl)-4H-1-benzopyran-4-one,

6-[5-(dipropylamino)pentoxy]-2-(4-methoxyphenyl)-4H-1-benzopyran-4-one,

2-(3,4-dimethoxyphenyl)-6-[5-(dipropylamino)pentoxy]-4H-1-benzopyran-4-one,

6-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[7-(4-hydroxypiperidinyl)heptoxy]-2-phenbenzopyran-4-one,

7-[4-(dimethylamino)butoxy]-2-phenyl-4H-1-benzopyran-4-one,

5-[6-(dimethylamino)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[4-(4-hydroxypiperidinyl)butoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[5-(4-hydroxypiperidinyl)pentoxy]-2-isobutyl-4H-1-benzopyran-4-one,

6-[8-(4-hydroxypiperdinyl)octoxy]-2-phenyl-4H-1-benzopyran-4-one,

2-(3-fluorophenyl)-6-[6-(4-hydroxypiperdinyl)hexoxy]-4H-1-benzopyran-4-one,

2-cyclohexyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,

6-[6-(4-hydroxypiperdinyl)hexoxy]-2-(3-methoxyphenyl)-4H-1-benzopyran-4-one

2-phenyl-6-(6-piperidinylhexoxy)-4H-1-benzopyran-4-one,

6-(6-morpholinylhexoxy)-2-phenyl-4H-1-benzopyran-4-one,

2-cyclopentyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,

2-(4-chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one

2-(3-chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one

6-[6-(4-hydroxypiperidinyl)hexoxy]-(4-methoxyphenyl)-4H-1-benzopyran-4-one,

2-cyclohexyl-6-(6-piperidinylhexoxy)-4H-1-benzopyran-4-one,

2-cyclohexyl-6-(6-morpholinylhexoxy)-4H-1-benzopyran-4-one,

7-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one,

7-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[6-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

2-cyclohexyl-6-[6-(4-hydroxypiperidinyl)hexoxy)-3-methyl-4H-1-benzopyran-4-one,

6-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-2-cyclopentyl-4H-1-benzopyran-4-one,

2-cyclopentyl-6-(6-piperidinyl)hexoxy-4H-1-benzopyran-4-one,

2-(4-fluorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one

2-cyclobutyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,

2-cyclobutyl-6-6-piperidinylhexoxy)-4H-1-benzopyran-4-one,

6-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-2-cyclobutyl-4H-1-benzopyran-4-one,

2-(3-chlorophenyl)-6-[6-(4-(4-chlorophenyl)4-hyroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,

2-(3-chlorophenyl)6-(6-piperidinyl)hexoxy]-4H-1-benzopyran-4-one,

2-(3-chlorophenyl)-6-6-piperidinyl)hexoxy-4H-1-benzopyran-4-one,

2-(3-chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one

6-[6-(4-hydroxypiperidinyl)hexoxy]-2-(2-thienyl)-4H-1-benzopyran-4-one,

6-(6-piperidinyl)-2-(2-thienyl)-4H-1-benzopyran-4-one,

5-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-2-(2-thienyl)-4H-1-benzopyran-4-one,

6-[6-(4-methylpiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

(±)-6-[6-(3-hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methoxy-2-phenyl-4H-1-benzopyran-4-one

5-[4-(4-Hydroxypiperidinyl)butoxy]-2-phenyl-4H-1-benzopyran-4-one,

5-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one,

5-[3-(4-hydroxypiperidinyl)propoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[6-(N,N-Benzylmethylamino)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-(Pyrrolidylhexoxy)-2-phenyl-4H-1-benzopyran-4-one,

6-(6-Hexamethyleneiminohexoxy)-2-phenyl-4H-1-benzopyran-4-one,

5-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[6-4-(2-Hydroxyethyl)piperazinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[5-(Dimethylamino)pentoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[6-(Diethylamino)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[6-(4-(4-Chlorophenyl)piperazinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

7-[8-(4-Hydroxypiperidinyl)octoxy]-2-phenyl-4H-1-benzopyran-4-one,

7-[4-(4-hydroxypiperidinyl)butoxy]-2-phenyl-4H-1-benzopyran-4-one,

7-[7-(4-hydroxypiperidinyl)heptoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-(6-piperidinylhexoxy)-2-(3-pyridyl)-4H-1-benzopyran-4-one,

6-(6-piperidinylhexoxy)-2-(4-pyridyl)-4H-1-benzopyran-4-one,

6-[6-(4-Hydroxypiperidinyl)hexoxy]-2-(4-pyridyl)-4H-1-benzopyran-4-one,

6-[6-(4-Hydroxypiperidinyl)hexoxy]-2-(3-pyridyl)-4H-1-benzopyran-4-one,

6-[4-dimethylamino)butoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[5-(4-hydroxypiperidinyl)pentoxyl]-2-(3,4-dimethoxyphenyl)-4H-1-benzopyran-4-one,

6-[5-(4-hydroxypiperidinyl)pentoxyl]-2-cyclohexyl-4H-1-benzopyran-4-one,

6-[5-(dipropylamino)pentoxy]-2-(4-methoxyphenyl)-4H-1-benzopyran-4-one,

6-[5-(dipropylamino)pentoxy]-2-(3,4-dimethoxyphenyl)-4H-1-benzopyran-4-one,

6-[6-(4-hydroxypiperidinyl)hexoxy]-2-cyclohexyl-4H-1-benzopyran-4-one,

2-(4-chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy-4H-1-benzopyran-4-one,

6-[6-(4-(4-chloropentyl)-1,2,3,6-tetrahydropyridyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

6-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-2-cyclophenyl-4H-1-benzopyran-4-one,

2-(3-chlorophenyl)-6-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,

and their pharmaceutically acceptable salts and hydrates.

Preferred compounds of the invention include:

5-[6-(dimethylamino)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

7-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one,

7-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

5-[6-(dimethylamino)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

7-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one,

7-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

5-[4-(4-Hydroxypiperidyl)butoxy]-2-phenyl-4H-1-benzopyran-4-one,

5-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one,

5-[3-(4-hydroxypiperidinyl)propoxy]-2-phenyl-4H-1-benzopyran-4-one,

5-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,

7-[8-(4-Hydroxypiperidinyl)octoxy]-2-phenyl-4H-1-benzopyran-4-one,

7-[4-(4-hydroxypiperidinyl)butoxy]-2-phenyl-4H-1-benzopyran-4-one,

7-[7-(4-hydroxypiperidinyl)heptoxy]-2-phenyl-4H-1-benzopyran-4-one; or

one of their pharmaceutically acceptable salts or hydrates.

Preferred compounds of the invention also include:

2-cyclohexyl-6-(6-piperidinylhexoxy)-4H-1-benzopyran-4-one,benzopyran-4-one,

6-[6-(4-hydroxypiperidinyl)hexoxy-4H-1-benzopyran-4-one,

2-cyclohexyl-6-[6-(4-hydroxypiperidinyl)hexoxy)-3-methyl-4H-1-benzopyran-4-one,

2-cyclopentyl-6-(6-piperidinyl)hexoxy-4H-1-benzopyran-4-one,

or one of their pharmaceutically acceptable salts or hydrates.

DETAILED DESCRIPTION OF THE INVENTION

The presently invented compounds that bind at sigma sites have thefollowing Formula I: ##STR2## in which:

X is --NR¹ R², ##STR3##

R¹ and R² are selected from the group consisting of --H, --C₁₋₆ alkyl, ahydroxy-substituted C₁₋₆ alkyl, and benzyl, provided R¹ and R² are notH;

R³ and R⁴ are selected from the group consisting of --H, --OH, C₁₋₄alkyl, hydroxy-substituted C₁₋₄ alkyl, benzyl, phenyl optionallysubstituted with --OH, --Cl, --F, --OC₁₋₄ alkyl, --C₁₋₄ alkyl, --CF₃,and any accessible combination thereof;

R⁵ is selected from the group consisting of --H, --C₁₋₆ alkyl,hydroxy-substituted C₁₋₆ alkyl, phenyl optionally substituted with --OH,--Cl, --F, --OC₁₋₄ alkyl, --CF₃, and any accessible combination thereof;

R⁶ is selected from the group consisting of phenyl optionallysubstituted with --OH, --Cl, --F, --OC₁₋₄ alkyl, --C₁₋₄ alkyl, --CF₃,and any accessible combination thereof;

m is 1, 2, or 3;

A¹, A², A³, and A⁴ independently are O or S;

Y is selected from the group consisting of cycloC₃₋₇ alkyl, C₁₋₆ alkyl,thienyl, pyridyl, furanyl, quinolyl, phenyl optionally substituted with--OH, --Cl, --F, --OC₁₋₄ alkyl, C₁₋₄ alkyl, --CF₃, and any accessiblecombination thereof;

Z is --H, C₁₋₄ alkyl, or --OR⁷ ;

R⁷ is --H or C₁₋₄ alkyl; and

B is C₄₋₁₀ alkyl; or pharmaceutically acceptable salts or hydratesthereof; provided that when B is (CH₂)₄, X is not N(CH₃)₂, N(CH₂ CH₃)₂,piperidinyl, morpholinyl, pyrrolidinyl, or substituted piperazinyl.

As used in the specification and claims "accessible combination thereof"means any combination of substituents that is available by chemicalsynthesis and is stable and C_(I-I') alkyl means a straight or branched,saturated or unsaturated hydrocarbon having I to I' carbon atoms where Iand I' are integers.

Preferred compounds have the following Formula (II) ##STR4## in which nis 4 to 10 and X, Y, and Z are as defined in Formula I.

Also preferred are Formula I or Formula II compounds wherein B is C₅₋₁₀alkyl, especially C₅₋₈ alkyl and C₆ alkyl.

Other preferred compounds are Formula II compounds wherein Z is --CH₃ orother C₁₋₄ alkyl, or --OR⁷ and Y is phenyl. Especially preferred aresuch compounds wherein X is 4-hydroxypiperidinyl or piperidinyl,particularly those wherein Z is CH₃.

In another preferred embodiment when X is --NR¹ R², ##STR5## as definedherein, and Z is hydrogen then Y is not a C₁₋₆ alkyl.

Formula I compounds are prepared from corresponding substitutedhydroxychromone compounds by processes such as shown in Scheme I, below.The starting hydroxychromone compounds are known and described inpublished references and can be purchased or readily prepared. In SchemeI, Z¹ and Y¹ are Z and Y in Formula I or substituents readilyconvertible to Z and Y. ##STR6##

Scheme I illustrates reaction of a substituted hydroxy chromone (A) with1-bromo-5-chloropentane to yield a substituted chloropentoxy chromone(B). In this reaction 1-bromo-5-chloropentane is replaced by selecteddihalo C₄₋₁₀ alkyls to yield Formula I compounds wherein B is other than(CH₂)₅.

Formula (B) compounds are then reacted with, for example, sodium iodideto yield compounds of Formula (C). Formula (D) compounds are prepared byreacting Formula (C) compounds with 4-hydroxypiperidine or are preparedby reacting Formula (B) compounds in the presence of sodium iodide withan amine selected to yield the desired X substituent. Scheme 1 showsreaction with 4-hydroxypiperidine to yield (4-hydroxypiperidinyl)pentoxycompounds.

Formula I compounds wherein A² or A³ are sulfur are prepared byreplacing the Formula (A) compounds with their sulfur analogues. Thesesulfur analogues also are known and described in published referencesand can be purchased or readily prepared. Formula I compounds where A¹is sulfur are prepared by substituting Formula (A) compounds with theirthiol analogues. ##STR7##

Schemes II and III illustrate the synthesis of Formula (A) or Formula(B) compounds when the desired Formula (A) compounds are notcommercially available. Scheme II uses the Baker- Venkataraman (BV)rearrangement to make the desired Formula (A) or (B) compounds. Thedesired Y¹ group is introduced as an acid halide to give the diester ofFormula (E) which is then treated with base under anhydrous conditionsto induce the BV rearrangement. Subsequent acid treatment followed bytreatment with aqueous base to hydrolyse the ester of the chromonehydroxyl group Formula (A) compounds. Alternatively, the desired B groupfrom Formula I may be introduced before the BV rearrangement (shown herewith B=(CH₂)₅ to give a Formula (F) compound) followed by treatment withthe acid halide, the BV rearrangement, and acid treatment to give thedesired Formula B compound.

In the cases for Formula I compounds where Z=OH or OR and Y=phenyl orsubstituted phenyl, then the chemistry of Scheme III is used to prepareFormula (A) or (B) compounds. Condensation of the acetophenone (G) withan aldehyde gives an intermediate chalcone which is then subjected tothe Algar-Flynn-Oyamada (AFO) reaction (treatment with hydrogen peroxideunder basic conditions) to give the desired Formula (A) compounds whereZ¹ =OH. Alternatively, the desired B group of Formula I may beintroduced before the AFO reaction to give Formula (H) compounds. TheFormula (H) compounds are reacted with an aldehyde and then subjected tothe AFO reaction to give the desired Formula (B) compounds where Z¹ =OH.If it is desired that Z¹ =OR (where R is an alkyl group), then treatmentof the Formula (B) compound (where Z¹ =OH) with base and an alkylatingagent (illustrated here with methyl iodide) will give the desiredcompounds.

Pharmaceutically acceptable acid addition salts of the compounds areformed with strong or moderately strong organic or inorganic acids byknown methods. Exemplary of the salts which are included in thisinvention are maleate, fumarate, lactate, oxalate, methanesulfonate,ethansulfonate, benzenesulfonate, tartrate, citrate, hydrochloride,hydrobromide, sulfate, phosphate, quinate, and nitrate salts.

The Formula I and Formula II compounds are potent and selective forsigma binding sites and are effective in preclinical screens predictiveof antipsychotic activity. The potency of these compounds in blockingradio ligand binding to sigma receptors was determined using the sigmareceptor binding assay described in Example 77. In vivo antipsychoticpotential was measured using two standard, accepted behavioral tests.The two tests used were: ( 1) Reversal of Amphetamine-InducedHyperlocomotion (Example 78); and (2) Reversal of Phencyclidine-InducedHyperlocomotion (Example 79). Potency in these tests was contrasted withpotenoy to produce extrapyramidal side effects (Catalepsy test, Example80). Selected compounds of Formula (I) were evaluated in these tests andcompared to haloperidol, a widely-used antipsychotic agent; rimcazole,and BMY-14802, known sigma site binding agents; and clozapine, anatypical antipsychotic that appears relatively free of extrapyramidalside effects, but produces agranulocytosis upon chronic administrationthat limits its therapeutic potential.

The test data are shown in Table I below. As these data make clear,Formula I compounds are potent sigma binding site agents and areeffective in at least one of the in vivo tests predictive ofantipsychotic efficacy.

The compounds of Formula I and Formula III can be incorporated intoconvenient pharmaceutical dosage forms such as capsules, tablets, orinjectable preparations. Solid or liquid pharmaceutical carriers can beemployed. Solid carriers include starch, lactose, calcium sulfatedihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia,magnesium stearate, and stearic acid. Liquid carriers include syrup,peanut oil, olive oil, saline, and water. Similarly, the carrier ordiluent may include any prolonged release material, such as glycerylmonostearate or glyceryl distearate, alone or with a wax. The amount ofsolid carrier varies widely but, preferably, will be from about 25 mg toabout 1 g per dosage unit. When a liquid carrier is used, thepreparation will be in the form of a syrup, elixir, emulsion, softgelatin capsule, sterile injectable liquid such as an ampoule, or anaqueous or nonaqueous liquid suspension.

The pharmaceutical preparations are made following conventionaltechniques of a pharmaceutical chemist involving mixing, granulating,and compressing, when necessary, for tablet forms, or mixing, filling,and dissolving the ingredients, as appropriate, to give the desired oralor parenteral products.

Doses of the present compounds of Formula I and Formula III in apharmaceutical dosage unit as described above will be an efficacious,nontoxic quantity selected from the range of 0.1-100 mg/kg of activecompound, preferably 0.1-50 mg/kg. The selected dose is administered toa human patient expected to be benefited by a sigma binding site agentfrom 1-6 or more times daily, orally, rectally, by injection, orcontinuously by infusion. Oral dosage units for human administrationpreferably contain from 1 to 500 mg of active compound. Parenteraladministration, generally uses lower doses.

The method of this invention of producing antagonism of sigma receptersin mammals, including humans, comprises administering internally to asubject expected to be benefited by a sigma receptor antagonist aneffective amount therefore of a compound of Formula III. ##STR8## inwhich:

X is --NR¹ R², ##STR9##

R¹ and R² selected from the group consisting of --H, --C₁₋₆ alkyl, ahydroxy-substituted C₁₋₆ alkyl, and benzyl, provided R¹ and R² are notH;

R³ and R⁴ are selected from the group consisting of --H, --OH, C₁₋₄alkyl, hydroxy-substituted C₁₋₄ alkyl, benzyl, phenyl optionallysubstituted with --OH, --Cl, --F, --OC₁₋₄ alkyl, --C₁₋₄ alkyl, --CF₃,and any accessible combination thereof;

R⁵ is selected from the group consisting of --H, --C₁₋₆ alkyl,hydroxy-substituted C₁₋₆ alkyl, phenyl optionally substituted with --OH,--Cl, --F, --OC₁₋₄ alkyl, --CF₃, and any accessible combination thereof;

R⁶ is selected from the group consisting of phenyl optionallysubstituted with --OH, --Cl, --F, --OC₁₋₄ alkyl, --C₁₋₄ alkyl, --CF₃,and any accessible combination thereof;

m is 1, 2, or 3;

A¹, A², A³, and A⁴ independently are O or S;

Y is selected from the group consisting of cycloC₃₋₇ alkyl, C₁₋₆ alkyl,thienyl, pyridyl, furanyl, quinolyl, phenyl optionally substituted with--OH, --Cl, --F, --OC₁₋₄ alkyl, C₁₋₄ alkyl, --CF₃, or any accessiblecombination thereof;

Z is --H, C₁₋₄ alkyl, or --OR⁷ ;

R⁷ is --H or C₁₋₄ alkyl; and

B is C₄₋₁₀ alkyl;

or pharmaceutically acceptable salts or hydrates thereof; provided thatwhen B is (CH₂)₄, X is not N(CH₃)₂, N(CH₂ CH₃)₂, piperidinyl,morpholinyl, pyrrolidinyl, or substituted piperazinyl.

Included in this invention are Formula (IV) compounds which are usefulin preparing Formula (I) compounds: ##STR10## in which:

W is I, Br, or Cl;

Z¹ and Y¹ are Z and Y in Formula (I) or compounds readily convertible toZ and Y; and

A¹, A², and A³ are as in Formula (I).

The following examples are illustrative of Formula (I) compounds andtheir preparation, and are given to illustrate the invention, but arenot deemed to be limiting thereof. All percentages given throughout thespecification are based on 100% by weight of the formulation.

EXAMPLE 1 6-[4-(Dimethylaminolbutoxy]-2-phenyl-4H-1benzopyran-4-onehydrochloride

A mixture of 6-hydroxyflavone (5.0 g, 21 mmol), 1-bromo-4-chlorobutane(4.86 mL, 42 mmol), and potassium carbonate (12 g, 84 mmol) was refluxedin acetone for 24 hours. The solution was cooled to room temperature,filtered, and the solvent removed in vacuo. The residue was boiled withether and filtered. Cooling gave 6.1 g (89%) of6-(4-chlorobutoxy)-2-phenyl-4H-1-benzopyran-4-one as a white solid.

A mixture of 6-(4-chlorobutoxy)-2-phenyl-4H-1-benzopyran-4-one (3.0 g, 9mmol) and sodium iodide (1.5 g, 10 mmol) in 125 mL of 2-butanone wasrefluxed for 96 hours. The solution was cooled to room temperature,filtered, and the solvent was removed in vacuo. The residue was stirredwith 250 mL of dichloromethane and filtered. Removal of the solvent invacuo gave the iodoflavone as a light yellow solid (3.8 g, 99%) that wasused without further purification.

A mixture of 6-(4-iodobutoxy)-2-phenyl-4H-1-benzopyran-4-one (3.8 g, 9mmol) and 40% aqueous dimethylamine (30 mL, 24 mmol) was refluxed in 100mL of ethanol for 24 hours. The reaction mixture was cooled to roomtemperature (22° C.) and made basic with saturated aqueous sodiumbicarbonate. The solution was concentrated in vacuo to approximatelyhalf its volume and extracted with ether. The combined ether layers weredried over sodium sulfate and the solvent removed in vacuo to give ayellow solid which was recrystallized to give 1.4 g of the free base aswhite crystals.

The free base (0.98 g, 28 mmol) was dissolved in 1 75 mL of ether and 29mL of a 1.0 M solution of hydrogen chloride in ether was added. Theresulting white precipitate was collected, washed with ether, and driedin vacuo to give 1.03 g of6-[4-(dimethylamino)butoxy]-2-phenyl-4H-benzopyran-4-one hydrochloride:mp 215°-219° C.

EXAMPLE 2 6-[8-Dimethylamino)octoxy]3-2-phenyl-4H-1-benzopyran-4-one

A mixture of 5.0 g (21 mmol) of 6-hydroxyflavone, 22.8 g (84 mmol) of1,8-dibromooctane, and 1 1.6 g (84 mmol) of potassium carbonate wasrefluxed in 250 mL of acetone for 48 hours. The reaction mixture wascooled to room temperature and filtered. The solutions were concentratedand cooled and 6.7 g of 6-(8-bromooctoxy)-2-phenyl-4H-benzopyran-4-onewas collected in two crops. A mixture of6-(8-bromooctoxy)-2-phenyl-4H-benzopyran-4-one (1.0 g, 2.3 mmol) anddimethylamine (40% wt./H₂ O, 3.0 mL) was refluxed in ethanol (15 mL) for2 hours. The reaction mixture was cooled to room temperature and then 5mL of saturated sodium bicarbonate was added. The solvent was removed invacuo and the residue triturated with 100 mL of ether. The mixture wasfiltered and the solutions were concentrated and cooled to give 0.6 g of6-[8-(dimethylamino)octoxyl]-2-phenyl-4H-1-benzopyran-4-one: mp 73°-75°C.

EXAMPLE 36-[6-(4-(2-Hydroxyethyl)piperidinyl)hexoxy1-2-phenyl-4H-1-benzopyran-4-onehydrochloride

A mixture of 6-(6-chlorohexoxy)flavone (Prepared from 6-hydroxyflavoneand 1-bromo-6-chlorohexane by a manner similar to6-(4-chlorobutoxy)flavone described in Example 1.) (2.00 g, 5.6 mmol),4-(2-hydroxyethyl)piperidine (1.09 g, 8.4 mmol), sodium iodide (0.92 g,6.1 mmol), and potassium carbonate (1.16 g, 8.4 mmol) in anhydrous DMFwas stirred at 80°-90° C. for 24 hours. The reaction was cooled to roomtemperature and water (300 mL) was added to the flask. The resultingprecipitate was collected by filtration and dissolved in methylenechloride (350 mL). This solution was washed with water (2×150 mL), brine(2×150 mL) and then the solution was dried over sodium sulfate. Removalof the solvent gave 2.32 g of the free base. The free base was dissolvedin hot EtOAc and the solution filtered. Then 1 equivalent of a 1Manhydrous solution of HCl in ether (Aldrich Chemical Co.) was added. Themixture was cooled in the freezer for 1 hour and the resulting solid wascollected by vacuum filtration and recrystallized from methyl alcohol togive 6-[6-(4-(2-hydroxyethyl)piperidylhexoxy)]flavone hydrochloridewhich was dried over P205 in high vacuum at 100° C. (yield=2.29 g, 76%):mp 204°-206° C.

EXAMPLE 4 6-[6-Dimethylamino)hexoxy1-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 1 from6-hydroxyflavone, 1-bromo-6-chlorohexane, and dimethylamine: mp182°-185° C. (dec).

EXAMPLE 56-[6-(2-Hydroxyethylmethylamino)hexoxy1-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 1 from6-hydroxyflavone, 1-bromo-6-chlorohexane, and 2-hydroxyethylmethylamine:mp 134°-137° C.

EXAMPLE 66-6(4-hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 1 from6-hydroxyflavone, 1-bromo-6-chlorohexane and 4-hydroxypiperidine: mp219°-221° C.

EXAMPLE 7 6-[7-(Dimethylamino)heptoxy1-2-phenyl-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 2 from6-hydroxyflavone, 1,7-dibromoheptane and dimethylamine: mp 90°-91° C.

EXAMPLE 8 6-[9-(Dimethylamino)nonoxy1-2-phenyl-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 2 from6-hydroxyflavone, 1,9- dibromononane and dimethylamine: mp 52°-53° C.

EXAMPLE 96-[9-(4-Methylpiperazinyl)nonoxy1-2-phenyl-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 2 from6-hydroxyflavone, 1,9-dibromononane and 4-methyl piperazine: mp 77°-80°C.

EXAMPLE 10 6-[10-(Dimethylamino)decoxy]-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 2 from6-hydroxyflavone, 1,10-dibromodecane and dimethylamine: mp158°-160° C.

EXAMPLE 112-Cyclopentyl-6-[6-(4-Hydroxypiperidyl)hexoxy1-4H-1-benzopyran-4-onehydrochloride

A mixture of 2',5'-dihydroxyacetophenone (150 g), 1-bromo-6-chlorohexane(186 g), and potassium carbonate (186 g) in 2500 mL of 2-butanone wasrefluxed for 16 hours. The solvent was removed in vacuo and the residuewas stirred with 1000 mL of methylene chloride. After filtration, thefiltrate was washed with 10% KOH (250 mL), water (250 mL), and brine(250 mL). The solution was dried over magnesium sulfate and the solventwas removed to give an oil which solidified overnight to give 210 g of5'-(6-chlorohexoxy)-2'-hydroxyacetophenone as a yellow solid.

The acetophenone (63.7 g) was dissolved in 450 mL of pyridine. Thencyclopentane carbonyl chloride (45 g) was added. The solution was heatedat 75° C. for 1.5 hours and then poured into 1200 mL of 3N HCl. Thesolution was extracted with ethyl acetate (3×500 mL). The combinedorganic layers were extracted with 3N HCl (2×500 mL), water (500 mL), 5%potassium carbonate (2×500 mL), and water (500 mL). After drying overmagnesium sulfate the solvent was removed to give the ester as an oil(80.3 g) which was used directly in the next step.

Sodium hydride (7.9 g) was suspended in 400 mL of anhydrous DMF and themixture was cooled to 0° C. where a solution of 80.3 g of the ester in200 mL of anhydrous DMF was added dropwise. The mixture was stirred for2 hours and then was quenched by the addition of 110 mL of acetic acid.This mixture was then poured into 1000 mL of a 1:1 solution of water andbrine. This solution was extracted by ether (3×500 mL). The combinedether layers were washed with water (2×500 mL) and brine (2×500 mL) andthen dried over magnesium sulfate. Removal of the solvent gave thediketone as a yellow solid (79.4 g).

The diketone was suspended in a solution of 4 mL of sulfuric acid in 400mL of acetic acid. The mixture was refluxed for 3 hours. The solvent wasremoved in vacuo and the residue was dissolved in 800 mL of ethylacetate. The solution was washed with water (400 mL), saturated sodiumbicarbonate (2×500 mL) and brine (500 mL). After drying the solutionover magnesium sulfate, the solvent was removed invacuo to give a solidwhich was recrystallized from ethyl acetate:hexane to give 31.2 g of6-(6-chlorohexoxy)-2-cyclopentyl-4H-1-benzopyran-4-one.

The reaction between6-(6-chlorohexoxy)-2-cyclopentyl-4H-1-benzopyran-4-one and4-hydroxypiperidine was carried out in a manner similar to that ofExample 3: mp 125°-126° C.

EXAMPLE 126-[5-(4-Hydroxypiperidinyl)pentoxy]-2(4-methoxyphenyl-)4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, 4 -methoxybenzoyl chloride,1-bromo-5-chloropentane, and 4-hydroxypiperidine: mp 138°-139° C.

EXAMPLE 13 2-(3,4-Dimethoxyohenyl)-6-5-(4-hydroxypiperidinyl)pentoxy1-H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone,3,4-dimethoxybenzoyl chloride,1-bromo-5-chloropentane, and 4-hydroxypiperidine: mp 154°-155° C.

EXAMPLE 142-Cyclohexyl-6-5-(4-hydroxypiperidinyl)pentoxy1-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, cyclohexanecarbonyl chloride,1-bromo-5-chloropentane, and 4-hydroxypiperidine: mp 85°-86° C.

EXAMPLE 156-[5-(Dipropylamino)pentoxy]-2-(3-methoxyphenyl)-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, 3-methoxybenzoyl chloride,1-bromo-5-chloropentane, and di-n-propyl amine: mp 80°-81° C.

EXAMPLE166-[5-(Dipropylamino)pentoxy]-2-(4-methoxyphenyl)-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 11 from2',5'-acetophenone, 4-methoxybenzoyl chloride, 1-bromo-5-chloropentane,and di-n- propylamine: mp 63°-64° C.

EXAMPLE 172-(3,4-Dimethoxyphenyl)-6-[5-dipropylamino)pentoxyl]-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 11 from2',5'dihydroxyacetophenone, 3,4-dimethoxybenzoyl chloride,1-bromo-5-chloropentane, and di-n-propylamine: mp 158°-159° C.

EXAMPLE 186-[5-(Hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 3 from6-hydroxyflavone, 1-bromo-5-chloropentane and 4-hydroxypiperidine: mp128°-129° C.

EXAMPLE 196-[7-(4-Hydroxypiperidinyl)heptoxy]-2-phenyl-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 2 from6-hydroxyflavone, 1-bromo-7-chloroheptane and 4-hydroxypiperidine: mp135°-136° C.

EXAMPLE 20 7-[4-(Dimethylamino)butoxy]-2-phenyl-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 1 from7-hydroxyflavone, 1-bromo-4-chlorobutane and dimethylamine: mp 95°-96°C.

EXAMPLE 21 5-[6-(Dimethylamino)hexoxy]-2-phenyl-4H-1-benzopyran-4-onehydrochloride

To a solution of 5-hydroxyflavone (5.24 9) in 10 mL of dry DMF was added1 equivalent of sodium hydride. The mixture was stirred until theevolution of hydrogen ceased. Then two equivalents of1-bromo-6-chlorohexane were added and the solution was heated at 85° C.for approximately 72 hours. The mixture was then poured into 400 mL ofwater. A solid separated that was collected by filtration andrecrystallized from ether to give 1.75 g of a mixture of 5-(6-chlorohexoxy)flavone and 5-(6-bromohexoxy)flavone. This mixture was thenrefluxed with 1.11 g of sodium iodide in 2-butanone for 48 hours. Themixture was cooled to room temperature and the solvent removed on arotary evaporator. The residue was extracted with methylene chloride.Removal of the methylene chloride on a rotary evaporator gave5-(6-iodohexoxy)flavone (1.5 g).

This compound then was dissolved in 50 mL of ethanol and refluxed with5.5 mL of 40% aqueous dimethylamine overnight. Saturated sodiumbicarbonate was added and then the solvent was removed on a rotaryevaporator. The residue was extracted with ethyl acetate and the solventremoved to give the free base as a white solid. The solid was dissolvedin ethanol and ethereal HCl was added. The product was collected byfiltration and washed with ethanol and then with ether: mp 166°-68° C.

EXAMPLE 226-[4-(4-Hydroxypiperidinyl)butoxy]-2-phenyl-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 3 from6-hydroxyflavone, 1-bromo-4-chlorobutane and 4-hydroxyflavone: mp124°-125° C.

EXAMPLE 236-[5-[4-Hydroxypiperidinyl)pentoxy]-2-isobutyl-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, isobutyryl chloride,1-bromo-5-chloropentane, and 4-hydroxypiperidine: mp 98°-99° C.

EXAMPLE 246-[8-(4-Hydroxypiperidinyl)octoxy1-2-phenyl-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 2 from6-hydroxyflavone, 1,8-dibromooctane and 4-hydroxypiperidine: mp 57°-58°C.

EXAMPLE 252-(3-Fluorophenyl)-6-6-(4-hydroxypiperidinyl)hexoxy1-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, 3-fluorobenzoyl chloride,1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp 136°-137° C.

EXAMPLE 262-Cyclohexyl-6-[6-4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, cyclohexanecarbonyl chloride,1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp 155°-156° C.

EXAMPLE 276-[6-(4-Hyroxypiperidinyl)hexoxy-2-(3-methoxyphenyl)-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, 3-methoxybenzoyl chloride,1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp 119°-120° C.

EXAMPLE 28 2-Phenyl-6-(6-piperidinylhexoxy)-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 3 from6-hydroxyflavone, 1-bromo-6-chlorohexane and piperidine: mp 176°-178° C.

EXAMPLE 29 6-(6-Morpholinylhexoxy)-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 3 from6-hydroxyflavone, 1-bromo-6-chlorohexane and morpholine: mp167°-170° C.

EXAMPLE 306-[5-(4-Hydroxypiperidyl)pentoxy1-2-(3-methoxyphenyl)-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, 3-methoxybenzoyl chloride,1-bromo-5-chloropentane, and 4-hydroxypiperidine: mp 115°-116° C.

EXAMPLE 312-(4-Chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy1-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, 4-chlorobenzoyl chloride,1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp 127°-128° C.

EXAMPLE 322-(3-Chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy1-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, 3-chlorobenzoyl chloride,1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp 120°-121° C.

EXAMPLE 336-(4-Hydroxypiperidinyl)hexoxy1-2-(4-methoxyphenyl)-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, 4-methoxybenzoyl chloride,1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp 134°-135° C.

EXAMPLE 34 2-Cyclohexyl-6-(piperidinylhexoxy)-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, cyclohexanecarbonyl chloride,1-bromo-6-chlorohexane, and piperidine: mp 164°-165° C.

EXAMPLE 35 2-Cyclohexyl-6-(6-morpholinylhexoxy)-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, cyclohexanecarbonyl chloride,1-bromo-6-chlorohexane, and morpholine: mp 167°-168° C.

EXAMPLE 367-[5-(4-Hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 3 from7-hydroxyflavone, 1-bromo-5-chloropentane, and 4-hydroxypiperidine: mp94°-95° C.

EXAMPLE 377-[6-(4-Hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 3 from7-hydroxyflavone, 1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp130°-131° C.

EXAMPLE 386[-(4-Chlorophenyl)-1,2,3,6-tetrahydropyridyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 3 from6-hydroxyflavone, 1-bromo-6-chlorohexane, and4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine: mp 213°-216° C.

EXAMPLE 396-[6-(4-Hydroxypiperidinyl)hexoxy]-3-methyl-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxypropiophenone, benzoyl chloride, 1-bromo-6-chlorohexane,and 4-hydroxypiperidine: mp 175°-176° C.

EXAMPLE 402-Cyclohexyl-6-[6-(4-hydroxypiperidinyl)hexoxy1-3-methyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxypropiophenone, cyclohexanecarbonyl chloride,1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp 109°-110° C.

EXAMPLE 416-[6-(4-Chlorophenyl)-4-hydroxypiperidinyl)hexoxy]2-cyclopentyl-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, cyclopentanecarbonyl chloride,1-bromo-6-chlorohexane, and 4-(4-chlorophenyl)-4-hydroxypiperidine: mp127°-128° C.

EXAMPLE 42 2-Cyclopentyl-6-[6-piperidinyl)hexoxy-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, cyclopentanecarbonyl chloride,1-bromo-6-chlorohexane, and piperidine: mp 138°-139° C.

EXAMPLE 432-(4-Fluorophenyl)-6-[6-4-hydroxypiperidinyl)hexoxy1-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, 4-fluorobenzoyl chloride,1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp 130°-131° C.

EXAMPLE 442-Cyclobutyl-6-[6-(4-hydroxypiperidinyl)hexoxyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, cyclobutanecarbonyl chloride,1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp 111°-113° C.

EXAMPLE 45 2-Cyclobutyl-6-(6-piperidinylhexoxy)-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, cyclobutanecarbonyl chloride,1-bromo-6-chlorohexane, and piperidine: mp 165°-166° C.

EXAMPLE 466-[6-(4-Chlorophenyl)-4-hydroxypiperidinyl)-hexoxy1-2-cyclobutyl-4H-1-benzopyran-4-one

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, cyclobutanecarbonyl chloride,1-bromo-6-chlorohexane, and 4-(4-chlorophenyl)-4- hydroxypiperidine: mp127°-128° C.

EXAMPLE 472-(2-Chlorophenyl)-6-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-hydrochloride

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, 2-chlorobenzoyl chloride,1-bromo-6-chlorohexane, and 4-4(4-chlorophenyl)-4-hydroxypiperidine: mp180°-181° C.

EXAMPLE 482-(2-Chlorophenyl)-6-6-piperidinyl)hexoxy-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 11 from 2',5'-dihydroxyacetophenone, 2-chlorobenzoyl chloride, 1-bromo-6-chlorohexane,and piperidine: mp 192°-193° C.

EXAMPLE 492-(2-Chlorophenyl)-6-(6-(4-hydroxypiperidinyl)hexoxy)-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, 2-chlorobenzoyl chloride,1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp 176°-177° C.

EXAMPLE 506-6-(4-Hydroxypiperidinyl)hexoxy1-2-(2-thienyl)-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, 2-thiophenecarbonyl chloride,1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp 211°-212° C.

EXAMPLE 51 6-Piperidinyl-2-(2-thienyl)-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, 2-thiophenecarbonyl chloride,1-bromo-6-chlorohexane, and piperidine: mp 184°-185° C.

EXAMPLE 526-[6-(4-(4-Chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-2-(2-thienyl)-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 11 from2',5'-dihydroxyacetophenone, 2-thiophenecarbonyl chloride,1-bromo-6-chlorohexane, and 4-4(4-chlorophenyl)-4-hydroxypiperidine: mp220°-221° C.

EXAMPLE 536-[6-(4-Methylpiperidinyl)hexoxy1-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 3 from6-hydroxyflavone, 1-bromo-6-chlorohexane, and 4-methylpiperidine mp209°-214° C.

EXAMPLE 54(±)-6-[6-(3-Hydroxypiperidinyl)hexoxy1-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by a method similar to Example 3 from6-hydroxyflavone, 1-bromo-6-chlorohexane, and 3-hydroxypiperidine: mp197°-202° C.

EXAMPLE 556-[6-(4-Hydroxypiperidinyl)hexoxy1-2-phenyl-4H-1-benzopyran-4-onehydrochloride

A mixture of 5'-(6-chlorohexoxy)-2'-hydroxyacetophenone (32 g) andbenzaldehyde (12 g) was dissolved in 250 mL of ethanol. A solution of 24g of sodium hydroxide dissolved in 40 mL of water was added. Thismixture was allowed to stand at room temperature for 6 hours. A solutionof 8 g of sodium hydroxide dissolved in 40 mL of water was added, thesolution was cooled to 15°-20° C., and then 20 mL of hydrogen peroxide(30% solution) was added and the solution was allowed to warm to roomtemperature and was stirred overnight. Then the solution's pH wasadjusted to 3 using hydrochloric acid. The yellow precipitate wascollected by vacuum filtration and washed with water, ethanol, and etherto give 16 g of 6-(6-chlorohexoxy)-3-hydroxy-4H- 1-benzopyran-4-one.Next, 10 g of 6-(6-chlorohexoxy)-3-hydroxy-4H-1-benzopyran-4-one wasdissolved in100 mL of tetrahydrofuran. Then 800 mg of sodium hydride wasadded followed by 8.3 mL of methyl iodide and the resulting solution wasstirred at room temperature for 48 hours. The reaction was poured intowater and extracted with ethyl acetate. The combined organic layers werewashed with water and then with brine. After drying over sodium sulfate,the solvent was removed to give 8 g of 6-(6-chlorohexoxy)-3-methoxy-4H-1-benzopyran-4-one.

A mixture of 2 g of 6-(6-chlorohexoxy)-3-methoxy-4H-1-benzopyran-4-one,1 g of sodium iodide, 0.6 g of potassium carbonate, and 1.4 g of4-hydroxypiperidine was refluxed in butanone for 96 hours. The solventwas removed and the residue stirred with ethyl acetate and filtered. Thesolution was washed with water and then dried over sodium sulfate. Thesolvent was removed to give an oil which was chromatographed over silicagel to give 2 g of6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methoxy-4H-1-benzopyran-4-one whichwas converted to the hydrochloride salt by dissolving in ethyl acetateand adding 1N ethereal HCL: mp 124°-125° C.

EXAMPLE 565-[4-(4-Hydroxypiperidinyl)butoxy]-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 21 from5-hydroxyflavone, 1-bromo-4-chlorobutane, and 4-hydroxypiperidine: mp161°-163° C.

EXAMPLE 575-[5-(4-hydroxypiperidinyl)pentoxy1-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 21 from5-hydroxyflavone, 1-bromo-5-chloropentane, and 4-hydroxypiperidine: mp184°-185° C.

EXAMPLE 585-[3-(4-hydroxypiperidinyl)propoxy]-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 21 from5-hydroxyflavone, 1-bromo-3-chloropropane, and 4-hydroxypiperidine: mp213°-215° C.

EXAMPLE 596-[6-(N,N-Benzylmethylamino)hexoxy]-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 3 from6-hydroxyflavone, 1-bromo-6-chlorohexane, and N,N-benzylmethylamine: mp178°-179 ° C.

EXAMPLE 60 6-(Pyrrolidylhexoxy)-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 3 from6-hydroxyflavone, 1-bromo-6-chlorohexane, and pyrrolidine: mp 179°-181 °C.

EXAMPLE 61 6-(6-Hexamethyleneiminohexoxy)-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 3 from6-hydroxyflavone, 1-bromo-6-chlorohexane, and hexamethyleneimine: mp173°-175 ° C.

EXAMPLE 625-[6-(4-hydroxypiperidinyl)hexoxyl-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 21 from5-hydroxyflavone, 1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp210°-211 ° C.

EXAMPLE 636-[6-(4-(2-Hydroxyethyl)piperazinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 3 from6-hydroxyflavone, 1-bromo-6-chlorohexane, and4-(2-Hydroxyethyl)piperazine: mp 239°-241° C.

EXAMPLE 64 6-[5-(Dimethylamino)pentoxy]-2-phenyl-4H-1-benzopyran-4-one

The compound was prepared by the method of Example 3 from6-hydroxyflavone, 1-bromo-5-chloropentane, and dimethylamine: mp 82°-83° C.

EXAMPLE 65 6-[6-(Diethylamino)hexoxy]-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 3 from6-hydroxyflavone, reagent, and diethylamine: mp 159°-161° C.

EXAMPLE 666-[6-(4-(4-Chlorophenyl)piperazinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 3 from6-hydroxyflavone, 1-bromo-6-chlorohexane, and4-(4-chlorophenyl)piperazine: mp 227°-229 ° C.

EXAMPLE 677-[8-(4-Hydroxypiperidinyl)octoxy]-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 2 from7-hydroxyflavone, 1,8-dibromooctane, and 4-hydroxypiperidine.

EXAMPLE 687-[4-(4-hydroxypiperidinyl)butoxy]-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 1 from7-hydroxyflavone, 1-bromo-4-chlorobutane, and 4-hydroxypiperidine: mp207°-209 ° C.

EXAMPLE 697-[7-(4-hydroxypiperidinyl)heptoxy]-2-phenyl-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 2 from7-hydroxyflavone, 1,7-dibromoheptane, and 4-hydroxypiperidine: mp143°-144 ° C.

EXAMPLE 70 6-(6-piperidinylhexoxy)-2-(3-pyridy)-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 11 from2',5'-dihydroxyacetophenone, 3-pyridylcarbonyl chloride,1-bromo-6-chlorohexane, and piperidine: mp 192°-193° C.

EXAMPLE 71 6-(6-piperidinylhexoxy)-2-(4-pyridy)-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 11 from2',5'-dihydroxyacetophenone, 4-pyridylcarbonyl chloride, and piperidine:mp 186°-187 ° C.

EXAMPLE 726-[6-(4-Hydroxypiperidinyl)hexoxy]-2-(4-pyridyl)-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 11 from2',5'-dihydroxyacetophenone, 4-pyridylcarbonyl chloride, and4-hydroxypiperidine: mp 165°-166 ° C.

EXAMPLE 736-[6-(4-Hydroxypiperidinyl)hexoxy]-2-(3-pyridyl)-4H-1-benzopyran-4-onehydrochloride

The compound was prepared by the method of Example 11 from2',5'-dihydroxyacetophenone, 3-pyridylcarbonyl chloride, and4-hydroxypiperidine:

EXAMPLE 74

An oral dosage form for administering the present compounds is producedby screening, mixing and filling into hard gelatin capsules theingredients in the proportions shown in Table II.

EXAMPLE 75

The sucrose, calcium sulfate dihydrate, and Formula I compound shown inTable III are mixed and granulated in the proportions shown with a 10%gelatin solution. The wet granules are screened, dried., mixed withstarch, talc and stearic acid, screened and compressed into a tablet.

EXAMPLE 76

6-[6-(4-Hydroxypiperidinyl)hexoxy]-3-methyl-2-phenyl-4H-1-benzopyran-4-one (75 mg) is dispersed in 25 ml of normal saline toprepare an injectable preparation.

EXAMPLE 77 Sigma and Dopamine Receptor Binding Assays

Two selective sigma receptor ligands, [³ H](+)-3-[3-hydroxyphenyl]-N-(1propyl)piperidine [(+)-3-PPP] and [³ H] Ditolylguanidine (DTG), wereused to label sigma sites in brain tissue.

The tissue preparation and assay conditions employed when using eitherof these ligands were essentially the same. Frozen whole guinea pigbrains (obtained from Pel-Freez, Rogers, Ariz.) were homogenized in 10volumes of ice-cold 0.32M sucrose. The resulting pellet was resuspendedin 10 volumes of ice-cold 50 mM Tris-HCl (pH 7.4), incubated at 37 ° C.for 30 minutes, and centrifuged at 22,000 × g for 20 minutes. The finaltissue suspension was made in 50 mM Tris-HCl (pH 7.4) to a concentrationof 20 mg original wet weight/mL. 800 μL of tissue suspension was addedto tubes containing 5 nM [³ H] DTG or 4 nM [³ H] (+)-3-PPP, and either10 μM haloperidol (to determine non-specific binding) or test compound.The final assay volume was 1 mL. The assay tubes were gently vortexed,and the binding reaction was carried out for 45 minutes at roomtemperature. The reaction was terminated by rapid filtration overWhatman GF/B glass fiber filters, which were then rinsed 3x with 5 mL of50 mM Tris-HCl. Filter bound radioactivity was quantified using liquidscintillation spectrometry.

Dopamine receptor binding was determined using [³ H] sulpiride. Ratstriata were homogenized in 20 volumes of ice-cold 50 mM Tris-HCl (pH7.5), and the resulting homogenate was centrifuged at 48,000 × g for 10minutes. The resulting pellet was resuspended in the original volume of50 mM Tris HCl and centrifuged as previously described. The final pelletwas resuspended in 50 mM Tris-HCl (pH 7.5) containing 100 mM NaCl to atissue concentration of 3.75 mg origina10 wet weight/mL. 800 μL oftissue suspension was added to tubes containing 3 nM [³ H] sulpiride andeither 10 μM unlabeled haloperidol (to determine non-specific binding)or test compound. The binding reaction was terminated after 60 minutesat room temperature by rapid filtration over presoaked (0.3% PEI)Whatman GF/B glass fiber filters. The filters were then washed 3 × with5 mL of 50 mM Tris-HCl containing 100 mM NaCl, and filter boundradioactivity was quantified using liquid scintillation spectrometry.

The results of these receptor binding assays are given in Table I.

EXAMPLE 78 Reversal of Amphetamine-Induced Hyperlocomotion

Opto-varimex locomotor monitors (Columbus Instruments, Columbus, Ohio)were used to assess locomotor activity. The monitors consist of a 37×37cm square plexiglass open field surrounded by an outer enclosure housinga 15×15 array of infrared photobeams. Placement of the mouse in the openfield interrupts one or more beams. Movement is detected by successiveinterruption of more than one beam (setting: box size - 1). The monitorswere placed on separate shelves in a dark test room. An IBM compatiblecomputer (Compaq) monitored beam interruptions and calculated indices oflocomotor activity (distance travelled, time ambulating) and stereotypebehavior (number of small movements, time in stereotypy or smallmovements). Because the dose of amphetamine in these studies was too lowto produce selective increases in stereotyped behavior, distancetravelled was the primary dependent variable.

Male CFl mice (25°-30 g) were obtained from Harlan Sprague Dawley(Indianapolis, (N) and group-housed with free access to food and waterfor at least four days prior to testing. All tests took place during thelight period of a 12:12 hour light-dark cycle. Each daily test consistedof one group of mice receiving a vehicle injection and an injection ofamphetamine as the agonist. One group received two vehicle injections,and one or more groups received test compound plus amphetamine. Testcompounds or the appropriate vehicles were administered 20 minutes priorto the locomotor test in studies using an intraperitoneal (i.p.) routeof administration with mice, 30 minutes prior to test session forstudies using an i.p. route of administration to rats, 45 minutes priorto the test session for studies using an oral (p.o.) route ofadministration with mice and 55 minutes prior to the locomotor test forstudies using a p.o. route of administration to rats. Amphetamine (1.5mg/kg, i.p.) or saline vehicle was administered 10 minutes prior to thetest session for all studies.

For initial screening, compounds were administered i.p. to mice at oneor more doses, chosen either on the basis of potency of similarcompounds, or chosen by reference to toxic doses (e.g., 1/5 thecatalepsy TD₅₀). A dose of test drug was considered effective if themean distance travelled by the drug-plus-amphetamine treated mice fellmore than 2.33 standard errors (99% confidence limits of the drug-plusamphetamine group) below the mean for the vehicle-plus-amphetaminegroup. Compounds that appeared active in the initial screen werere-evaluated at a minimum of three doses, including the dose thatappeared effective in the initial screen. For this and all remainingstudies (i.e., oral activity, effects in rats) the minimally effectivedose (MED) was then estimated as the lowest dose for which a separatevariance I test indicated that distance travelled by thedrug-plus-amphetamine treated group differed significantly from distancetravelled by the vehicle-plus- amphetamine group (<0.05).

The test results for selected compounds are shown in Table I.

EXAMPLE 79 Reversal of Phencyclidine-lnduced Hyperlocomotion

The procedure and data analysis were identical to that reported abovefor reversal of amphetamine hyperlocomotion with the exception that 3mg/kg phencyclidine was injected in place of amphetamine 10 minutesprior to the test session. The test results are shown in Table I.

EXAMPLE 80 Induction of Haloperidol-like Catalypsy

Male CFl mice (25-30 g) (Harlan Sprague-Dawley) were injected with testcompound or the appropriate vehicle 30 minutes prior to the test. At thetime of the test the front paws of the mouse were placed on a 6 mmdiameter rod which was mounted between the side walls of the apparatus,39 mm above the floor. Gentle pressure was applied from the forefingerto immobilize the animal, with its back in a slightly arched (concave)position. The experimenter then released the mouse and recorded thelatency to recover normal posture, as defined by return of at least oneforepaw to the floor or placement of one hindlimb on the bar. A mousewas considered cataleptic if it did not recover normal posture within 30seconds. Each mouse was given up to three opportunities to demonstratecatalepsy. A minimum of 6 mice were tested at each drug dose and a TD₅₀for producing catalepsy was calculated according to the method ofLitchfield and Wilcoxin (1949). TD₅₀ values for lead compounds andreference compounds were confirmed in side-by-side studies by anexperimenter blind to treatment conditions. The test results are shownin Table I.

                                      TABLE I                                     __________________________________________________________________________    SUMMARY OF IN VITRO AND IN VIVO TESTING                                       Receptor Potency                                                              Drug   Sigma           Induced                                                (Name or                                                                             (IC.sub.50, nMol)                                                                       D.sub.2                                                                             Locomotion                                             Example No.)                                                                         DTG  PPP  (K.sub.i, nMol)                                                                     Amphetamine                                                                          PCP   Catalepsy                                 __________________________________________________________________________    Clozapine                                                                            15,000                                                                             34,600                                                                               350  1           NE (4)                                    Haloperidol                                                                           7    4        0.67                                                                              0.075  0.15  0.14                                   Rimcazole                                                                            1,620                                                                              1,400                                                                              22,520                                                                              20        >20                                                                              NE                                        BMY14802                                                                             237  319  3,000 15           NE                                        4      432  335  5,550 30     NE (30)  38                                     6      100  124  3,630   5.0     15    61                                     26      88   46  25,000                                                                              20              50                                     39      36   43  2,700 25           NE (250)                                  28     100   54  4,445 20        30    <30                                    34      54   32  7,650 10              30                                     37      45   70  6,000 30                                                     49      47   29  4,050 30                                                     29     713  237  18,700                                                                              10              38                                     __________________________________________________________________________     NE = no effect to dose shown                                             

                  TABLE II                                                        ______________________________________                                        Ingredients             Amounts                                               ______________________________________                                        6-[6-(4-Hydroxypiperidinyl)hexoxy]-                                                                   50 mg                                                 3-methyl-2-phenyl-4H-1-benzopyran-4-one                                       magnesium stearate       5 mg                                                 lactose                 75 mg                                                 ______________________________________                                    

                  TABLE III                                                       ______________________________________                                        Ingredients             Amounts                                               ______________________________________                                        6-[6-(4-Hydroxypiperidinyl)-hexoxy]-                                                                  100 mg                                                3-methyl-2-phenyl-4H-1-benzopyran-4-one                                       calcium sulfate dihydrate                                                                             20 mg                                                 sucrose                 150 mg                                                starch                  20 mg                                                 talc                     5 mg                                                 stearic acid             3 mg                                                 ______________________________________                                    

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of theclaims.

What is claimed is:
 1. A compound represented by the formula: ##STR11##in which: X is ##STR12## R³ and R⁴ are selected from the groupconsisting of --H, --C₁₋₄ alkyl, hydroxy-substituted C₁₋₄ alkyl, benzyl,phenyl optionally substituted with --OH, --Cl, --F, --OC₁₋₄ alkyl,--C₁₋₄ alkyl, --CF₃ ;m is 1, 2, or 3; A¹, A², A³, and A⁴ independentlyare O or S; Y is selected from the group consisting of cycloC₃₋₇ alkyl,phenyl optionally substituted with --OH, --Cl, --F, --OC₁₋₄ alkyl, C-₁₋₄alkyl, --CF₃ ; Z is --H, C₁₋₄ alkyl, or --OR⁷ ; R⁷ is --H or C₁₋₄ alkyl;and B is C₄₋₁₀ alkyl,or pharmaceutically acceptable salts or hydratesthereof; provided that when B is (CH₂)₄, X is [N(CH₃)₂, N(CH₂ CH₃)₂, ]not piperidinyl.
 2. A compound of claim 1 represented by the formula:##STR13## in which n is 4 to 10, and X, Y, and Z are as defined inclaim
 1. 3. A compound of claim 2 that is 6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methyl-2-phenyl-4H-1-benzopyran-4-one or one of its salts orhydrates.
 4. A compound of claim 2 that is 6-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one.
 5. A compound of claim 2 that is2-cyclohexyl-6-(6-piperidinylhexoxy)-4H-1-benzopyran-4-one or one of itspharmaceutically acceptable salts or hydrates.
 6. A compound of claim 2that is6-[-6-(4-hydroxypiperidinyl)hexoxy]-3-methyl-2-phenyl-4H-1-benzopyran-4-oneor one of its pharmaceutically acceptable salts or hydrates.
 7. Acompound of claim 2 that is2-cyclohexyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methyl-4H-1-benzopyran-4-oneor one of its pharmaceutically acceptable salts or hydrates.
 8. Acompound of claim 2 that is2-cyclopentyl-6-(6-piperidinyl)hexoxy-4H-1-benzopyran-4-one or one ofits pharmaceutically acceptable salts or hydrates.
 9. A compound ofclaim 2 that is:6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methyl-2-phenyl-4H-1-benzopyran-4-one, 6-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,6-[5-(4-hydroxypiperidinyl)pentoxy]-2-(3-methoxyphenyl)-4H-1-benzopyran-4-one,6-[5-(4-hydroxypiperidinyl)pentoxy]-2-(4-methoxyphenyl)-4H-1-benzopyran-4-one,2-(3,4-dimethoxyphenyl)-6-[5-(4-hydroxypiperidinyl)pentoxy]-4H-1-benzopyran-4-one, 2-cyclohexyl-6-[5-(4-hydroxypiperidinyl)pentoxy]-4H-1-benzopyran-4-one, 6-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one, 6-[7-(4-hydroxypiperidinyl)heptoxy]-2-phenyl-4H-1-benzopyran-4-one, 6-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one, 6-[4-(4-hydroxypiperidinyl)butoxy]-2-phenyl-4H-1-benzopyran-4-one, 6-[8-(4-hydroxypiperidinyl)octoxy]-2-phenyl-4H-1-benzopyran-4-one,2-(3-fluorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one, 2-cyclohexyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,6-[6-(4-hydroxypiperidinyl)hexoxy]-2-(3-methoxyphenyl)-4H-1-benzopyran-4-one, 2-phenyl-6-(6-piperidinylhexoxy]-4H-1-benzopyran-4-one, 2-cyclopentyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,2-(4-chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,2-(3-chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,6-[6-(4-hydroxypiperidinyl)hexoxy]-(4-methoxyphenyl)-4H-1-benzopyran-4-one, 2-cyclohexyl-6-(6-piperidinylhexoxy]-4H-1-benzopyran-4-one,2-cyclohexyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methyl-4H-1-benzopyran-4-one,6-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-2-cycloypentyl)-4H-1-benzopyran-4-one, 2-cyclopentyl-6-(6-piperidinyl)hexoxy]-4H-1-benzopyran-4-one,2-(4-fluorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one, 2-cyclobutyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one, 2-cyclobutyl-6-(6-piperidinylhexoxy)-4H-1-benzopyran-4-one,6-[6-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-2-cyclobutyl)-4H-1-benzopyran-4-one,2-(3-chlorophenyl)-6-[6-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one, 2-(3-chlorophenyl)-6-(6-piperidinyl)hexoxy]-4H-1-benzopyran-4-one,2-(3-chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,6-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-2-(2-thienyl)-4H-1-benzopyran-4-one, 6-[6-(4-methylpiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one, (±)-6-[6-(3-hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methoxy-2-phenyl-4H-1-benzopyran-4-one, 6-(Pyrrolidylhexoxy)-2-phenyl-4H-1-benzopyran-4-one,6-(5-(4-Hydroxypiperidinyl)pentoxyl]-2-(3,4-dimethoxyphenyl)-4H-1-benzopyran-4-one,6-[5-(4-hydroxypiperidinyl)pentoxyl]-2-cyclohexyl)-4H-1-benzopyran-4-one,6-[6-(4-hydroxypiperidinyl)hexoxyl]-2-cyclohexyl)-4H-1-benzopyran-4-one,2-(4-chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy-4H-1-benzopyran-4-one,6-[6-(4-4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy-2-cyclopentyl-4H-1-benzopyran-4-one,2-(3-chlorophenyl)-6-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy-4H-1-benzopyran-4-one,and their pharmaceutically acceptable salts andhydrates.
 10. A compound of claim 1 thatis:7-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one,7-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,5-[4-(4-Hydroxypiperidinyl)butoxy]-2-phenyl-4H-1-benzopyran-4-one,5-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one,5-[3-(4-hydroxypiperidinyl)propoxy]-2-phenyl-4H-1-benzopyran-4-one,5-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,7-[8-(4-Hydroxypiperidinyl)octoxy]-2-phenyl-4H-1-benzopyran-4-one,7-[4-(4-hydroxypiperidinyl)butoxy]-2-phenyl-4H-1-benzopyran-4-one,7-[7-(4-hydroxypiperidinyl)heptoxy]-2-phenyl-4H-1-benzopyran-4-one;orone of their pharmaceutically acceptable salts or hydrates.
 11. Apharmaceutical composition useful for producing antagonism of sigmareceptor sites comprising a pharmaceutical carrier and a compound ofclaim
 1. 12. A pharmaceutical composition useful for producingantagonism of sigma receptor sites comprising a pharmaceutical carrierand a compound of claim
 2. 13. A composition of claim 12 in which thecompound is6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methyl-2-phenyl-4H-1-benzopyran-4-one-orone of its pharmaceutically acceptable salts or hydrates.
 14. Acomposition of claim 12 in which the compound is6-(6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one or oneof its pharmaceutically acceptable salts or hydrates.
 15. A compositionof claim 12 in which the compound is2-cyclohexyl-6-(6-piperidinylhexoxy)-4H-1-benzopyran-4-one or one of itspharmaceutically acceptable salts or hydrates.
 16. A composition ofclaim 12 in which the compound is6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methyl-2-phenyl-4H-1-benzopyran-4-oneor one of its pharmaceutically acceptable salts or hydrates.
 17. Acomposition of claim 12 in which the compound is2-cyclohexyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methyl-4H-1-benzopyran-4-oneor one of its pharmaceutically acceptable salts or hydrates.
 18. Acomposition of claim 12 in which the compound is2-cyclopentyl-6-(6-piperidinyl)hexoxy-4H-1-benzopyran-4-one or one ofits pharmaceutically acceptable salts or hydrates.
 19. A method of claim12 in which the compoundis:6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methyl-2-cyclohexyl)-4H-1-benzopyran-4-one, 6-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl)-4H-1-benzopyran-4-one,6-[5-(4-hydroxypiperidinyl)pentoxy]-2-(3-methoxyphenyl)-4H-1-benzopyran-4-one,6-[5-(4-hydroxypiperidinyl)pentoxy]-2-(4-methoxyphenyl)-4H-1-benzopyran-4-one,2-(3,4-dimethoxyphenyl)-6-[5-(4-hydroxypiperidinyl)pentoxy]-4H-1-benzopyran-4-one,2-cyclohexyl)-6-[5-(4-hydroxypiperidinyl)pentoxy]-4H-1-benzopyran-4-one, 6-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one, 6-[7-(4-hydroxypiperidinyl)heptoxy]-2-phenyl-4H-1-benzopyran-4-one, 6-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one, 6-[4-(4-hydroxypiperidinyl)butoxy]-2-phenyl-4H-1-benzopyran-4-one, 6-[8-(4-hydroxypiperidinyl)octoxy]-2-phenyl-4H-1-benzopyran-4-one,2-(3-fluorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one, 2-cyclohexyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,6-[6-(4-hydroxypiperidinyl)hexoxy]-2-(3-methoxyphenyl-4H-1-benzopyran-4-one, 2-phenyl-6-(6-piperidinylhexoxy)-4H-1-benzopyran-4-one, 2-cyclopentyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,2-(4-chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,2-(3-chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,6-[6-(4-hydroxypiperidinyl)hexoxy]-(4-methoxyphenyl)-4H-1-benzopyran-4-one, 2-cyclohexyl-6-(6-piperidinylhexoxy)-4H-1-benzopyran-4-one,2-cyclohexyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methyl-4H-1-benzopyran-4-one,6-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-2-cyclopentyl)-4H-1-benzopyran-4-one, 2-cyclopentyl-6-(6-piperidinyl)hexoxy]-4H-1-benzopyran-4-one,2-(4-fluorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one, 2-cyclobutyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one, 2-cyclobutyl)-6-(6-piperidinylhexoxy)-4H-1-benzopyran-4-one,6-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-2-cyclobutyl)-4H-1-benzopyran-4-one,2-(3-chlorophenyl)-6-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl]-4H-1-benzopyran-4-one,2-(3-chlorophenyl)-6-(6-piperidinyl)hexoxy-4H-1-benzopyran-4-one,2-(3-chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one6-[6-(4-methylpiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,[(±)-6-[6-(3-hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methoxy-2-phenyl-4H-1-benzopyran-4-one6-(Pyrrolidylhexoxy)-2-phenyl-4H-1-benzopyran-4-one,6-[5-(4-hydroxypiperidinyl)pentoxy]-2-(3,4-dimethoxyphenyl)-4H-1-benzopyran-4-one,6-[5-(4-hydroxypiperidinyl)pentoxyl]-2-cyclohexyl-4H-1-benzopyran-4-one,6-[6-(4-hydroxypiperidinyl)hexoxyl]-2-cyclohexyl-4H-1-benzopyran-4-one,2-(4-chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxyl-4H-1-benzopyran-4-one6-[6-(4(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxyl]-2-cyclopentyl-4H-1-benzopyran-4-one,2-(3-chlorophenyl)-6-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl)-4H-1-benzopyran-4-one,andtheir pharmaceutically acceptable salts and hydrates.
 20. A compositionof claim 11 in which the compoundis:7-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H- 1-benzopyran-4-one,7-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-4H- 1-benzopyran-4-one,5-[4-(4-Hydroxypiperidinyl)butoxy]-2-phenyl-4H- 1-benzopyran-4-one,5-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H- 1-benzopyran-4-one,5-[3-(4-hydroxypiperidinyl)propoxy]-2-phenyl-4H- 1-benzopyran-4-one,5-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-4H- 1-benzopyran-4-one,7-[8-(4-hydroxypiperidinyl)octoxy]-2-phenyl-4H- 1-benzopyran-4-one,7-[4-(4-hydroxypiperidinyl)butoxy]-2-phenyl-4H- 1-benzopyran-4-one,7-[7-(4-hydroxypiperidinyl)heptoxy]-2-phenyl-4H- 1-benzopyran-4-one,oneof their pharmaceutically acceptable salts or hydrates.
 21. A method ofproducing sigma receptor antagonism in mammals that comprisesadministering to a subject an effective amount of a compound representedby the formula: ##STR14## in which: X is ##STR15## R³ and R⁴ areselected from the group consisting of --H, --C₁₋₄ alkyl,hydroxy-substituted C₁₋₄ alkyl, phenyl optionally substituted with --OH,--Cl, --F, --OC₁₋₄ alkyl, --CF₃ ;m is 1, 2, or 3; A¹, A², A³, and A⁴independently are O or S; Y is selected from the group consisting ofcycloC₃₋₇ alkyl, phenyl optionally substituted with --OH, --Cl, --F,--OC₁₋₄ alkyl, C-₁₋₄ alkyl, --CF₃ ; Z is --H, C₁₋₄ alkyl, or --OR⁷ ; R⁷is --H or C₁₋₄ alkyl; and B is C₄₋₁₀ alkyl,or pharmaceuticallyacceptable salts or hydrates thereof.
 22. A method of producing sigmareceptor blockage in mammals that comprises administering to a subjectin need of such blockage an effective amount of a compound representedby the formula: ##STR16## in which: X is ##STR17## R³ and R⁴ areselected from the group consisting of --H, C₁₋₄ alkyl,hydroxy-substituted C₁₋₄ alkyl, phenyl optionally substituted with --OH,--Cl, --F, --OC₁₋₄ alkyl, --CF₃ ;Y is selected from the group consistingof cycloC₃₋₇ alkyl, phenyl optionally substituted with --OH, --Cl, --F,--OC₁₋₄ alkyl, C-₁₋₄ alkyl, --CF₃ ; m is 1, 2, or 3; Z is --H, C₁₋₄alkyl, or --OR⁷ ; R⁷ is --H or C₁₋₄ alkyl; and n is 4 to 10;orpharmaceutically acceptable salts or hydrates thereof.
 23. A method ofclaim 22 in which the compound is6-[6-(4-hydroxpiperidinyl)hexoxy]-3-methyl-2-phenyl-4H-1-benzopyran-4-oneor one of its salts or hydrates.
 24. A method of claim 22 in which thecompound is6-[6-(4-hydroxpiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one.
 25. Amethod of claim 22 in which the compoundis2-cyclohexyl-6-(6-piperidinylhexoxy)-4H-1-benzopyran-4-one,6-[-6-(4-hydroxypiperidinyl)-hexoxy]-3-methyl-2-phenyl-4H-1-benzopyran-4-one,2-cyclohexyl-6-[6-(4-hydroxypiperidinyl)hexoxy)-3-methyl-4H-1-benzopyran-4-one,2-cyclopentyl-6-(6-piperidinyl)hexoxy-4H-1-benzopyran-4-one,or one oftheir pharmaceutically acceptable salts or
 26. A method of claim 22 inwhich the compoundis6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methyl-2-phenyl-4H-1-1-benzopyran-4-one, 6-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,6-[5-(4-hydroxypiperidinyl)pentoxy]-2-(3-methoxyphenyl)-4H-1-benzopyran-4-one,6-[5-(4-hydroxypiperidinyl)pentoxy]-2-(4-methoxyphenyl)-4H-1-benzopyran-4-one,2-(3,4-dimethoxyphenyl)-6-[5-(4-hydroxypiperidinyl)pentoxy]-4H-1-benzopyran-4-one,2-cyclohexyl-6-[5-(4-hydroxypiperidinyl)pentoxy]-4H-1-benzopyran-4-one,6-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one,6-[7-(4-hydroxypiperidinyl)heptoxy]-2-phenyl-4H-1-benzopyran-4-one,6-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-4H-1-benzopyran-4-one,6-[4-(4-hydroxypiperidinyl)butoxy]-2-phenyl-4H-1-benzopyran-4-one,6-[8-(4-hydroxypiperidinyl)octoxy]-2-phenyl-4H-1-benzopyran-4-one,2-(3-fluorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one2-cyclohexyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,6-[6-(4-hydroxypiperidinyl)hexoxy]-2-(3-methoxyphenyl)-4H-1-benzopyran-4-one,2-phenyl-6-(6-piperidinylhexoxy)-4H-1-benzopyran-4-one,2-cyclopentyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,2-(4-chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one2-(3-chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one6-[6-(4-hydroxypiperidinyl)hexoxy]-(4-methoxyphenyl)-4H-1-benzopyran-4-one,2-cyclohexyl-6-(6-piperidinylhexoxy)-4H-1-benzopyran-4-one,2-cyclohexyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methyl-4H-1-benzopyran-4-one,6-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-2-cyclopentyl-4H-1-benzopyran-4-one,2-cyclopentyl-6-(6-piperidinyl)hexoxy-4H-1-benzopyran-4-one,2-(4-fluorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one2-cyclobutyl-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one,2-cyclobutyl-6-(6-piperidinylhexoxy-4H-1-benzopyran-4-one,6-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-2-cyclobutyl-4H-1-benzopyran-4-one,2-(3-chlorophenyl)-6-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-2-cyclopentyl-4H-1-benzopyran-4-one,2-(3-chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one6-[6-(4-methylpiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,(±)-6-[6-(3-hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one,6-[6-(4-hydroxypiperidinyl)hexoxy]-3-methoxy-2-phenyl-4H-1-benzopyran-4-one6-(pyrrolidylhexoxy)-2-phenyl-4H-1-benzopyran-4-one,6-[5-(4-hydroxypiperidinyl)pentoxy]-2-(3,4-dimethoxyphenyl)-4H-1-benzopyran-4-one,6-[5-(4-hydroxypiperidinyl)pentoxy]-2-cyclohexyl-4H-1-benzopyran-4-one,6-[6-(4-hydroxypiperidinyl)hexoxy]-2-cyclohexyl-4H-1-benzopyran-4-one,2-(4-chlorophenyl)-6-[6-(4-hydroxypiperidinyl)hexoxy]-4H-1-benzopyran-4-one6-[6(4-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-2-cyclopentyl-4H-1-benzopyran-4-one,2-(3-chlorophenyl)-6-[6-(4-(4-chlorophenyl)-4-hydroxypiperidinyl)hexoxy]-2-cyclopentyl-4H-1-benzopyran-4-one,andtheir pharmaceutically acceptable salts and hydrates.
 27. A method ofclaim 21, in which the compoundis7-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-2-phenyl-4H-1-1-benzopyran-4-one,7-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-2-phenyl-4H-1-1-benzopyran-4-one,7-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-2-phenyl-4H-1-1-benzopyran-4-one,7-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-2-phenyl-4H-1-1-benzopyran-4-one,5-[4-(4-hydroxypiperidinyl)butoxy]-2-phenyl-2-phenyl-4H-1-1-benzopyran-4-one,5-[5-(4-hydroxypiperidinyl)pentoxy]-2-phenyl-2-phenyl-4H-1-1-benzopyran-4-one,5-[3-(4-hydroxypiperidinyl)propoxy]-2-phenyl-2-phenyl-4H-1-1-benzopyran-4-one,5-[6-(4-hydroxypiperidinyl)hexoxy]-2-phenyl-2-phenyl-4H-1-1-benzopyran-4-one,7-[8-(4-hydroxypiperidinyl)octoxy]-2-phenyl-2-phenyl-4H-1-1-benzopyran-4-one,7-[4-(4-hydroxypiperidinyl)butoxy]-2-phenyl-2-phenyl-4H-1-1-benzopyran-4-one,7-[7-(4-hydroxypiperidinyl)heptoxy]-2-phenyl-2-phenyl-4H-1-1-benzopyran-4-one; orone of their pharmaceutically acceptable salts orhydrates.